Submissions for variant NM_001035.3(RYR2):c.10266G>C (p.Gln3422His)

gnomAD frequency: 0.00001  dbSNP: rs368064371

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001704874	SCV000235273	uncertain significance	not provided	2022-01-25	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 201395; ClinVar); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009)
Invitae	RCV002516913	SCV000637471	uncertain significance	Catecholaminergic polymorphic ventricular tachycardia 1	2023-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 3422 of the RYR2 protein (p.Gln3422His). This variant is present in population databases (rs368064371, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with RYR2-related conditions. ClinVar contains an entry for this variant (Variation ID: 201395). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RYR2 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170263	SCV001332825	uncertain significance	Cardiomyopathy	2018-03-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001170263	SCV001355745	uncertain significance	Cardiomyopathy	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with histidine at codon 3422 of the RYR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a control individual who had no history of cardiac arrhythmia (PMID: 35819174). This variant has been identified in 4/241568 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002381601	SCV002691201	uncertain significance	Cardiovascular phenotype	2020-01-29	criteria provided, single submitter	clinical testing	The p.Q3422H variant (also known as c.10266G>C), located in coding exon 71 of the RYR2 gene, results from a G to C substitution at nucleotide position 10266. The glutamine at codon 3422 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469049	SCV002766118	uncertain significance	not specified	2022-11-18	criteria provided, single submitter	clinical testing	Variant summary: RYR2 c.10266G>C (p.Gln3422His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 241568 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.10266G>C in individuals affected with Catecholaminergic Polymorphic Ventricular Tachycardia and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.